Ezetimibe is a selective cholesterol absorption inhibitor, which is used in the adjuvant therapy of primary (heterozygote familiar and non-familiar) hypercholesterolemia together with dietetic control in combination with a HMG-CoA reduction inhibitor (statin), in case when statin monotherapy alone is insufficient.
Regarding physical-chemical properties of ezetimibe, it is white and crystalline powder, which is insoluble in water and in digestive juice, but soluble in organic solvents. Ezetimibe is a Class II type active substance according to the Biopharmaceutics Classification System, wherein the bioavailability depends on the dissolution rate of the active substance. To exhibit the therapeutical effect, a sufficient bioavailability is to be achieved in spite of its water insolubility. Several dissolution-enhancing processes are known in order to achieve sufficient bioavailability.
Amorphous ezetimibe is adsorbed on a polymer substrate or is obtained on said polymer as a solid amorphous dispersion according to EP 1799648 European patent application.
WO2008/063766 international patent application describes a composition, which contains a solid dispersion of amorphous ezetimibe and at least one dissolution rate increasing polymer. According to one aspect of this invention, ezetimibe and the dissolution rate increasing polymer are dissolved together in a common solvent or a solvent-mixture and thereafter the mixture is evaporated or spray-dried. According to another aspect of this invention, ezetimibe is dispersed in the molten dissolution-rate increasing polymer, and the molten mixture is spray congealed. According to a further aspect of this invention ezetimibe and the polymer are dissolved in a solvent mixture, wherein the solubility of the polymer is smaller in the less volatile solvent than in the other solvent, therefore the polymer precipitates earlier from the solution during evaporation or spray drying.
European patent application 1849459 describes a pharmaceutical composition, where the ezetimibe is co-milled with at least one hydrophilic excipient, e.g. a saccharide, polysaccharide, starch, pre-gelatinized starch. After milling the particle size d(0.5) of ezetimibe is below 25 μm.
According to WO 2007/01 1349 international patent application the bioavailability of poorly water soluble active ingredients, e.g. ezetimibe, is increased by intimately contacting said ingredient with a pharmaceutically acceptable sugar. In one aspect said intimate contacting is carried out by dissolving the sugar and granulating the active ingredient with the dissolved sugar.
US Patent Application 2007/0275052 describes a pharmaceutical composition, wherein the particle size d(90) of ezetimibe is below 25 μm in order to achieve sufficient solubility.
WO 2008/101723 international patent application describes a pharmaceutical composition, which contains amorphous ezetimibe dispersed uniformly in a hydrophilic polymer.
WO 2009/077573 international patent application relates to a suspension comprising ezetimibe micro-particles having small particle size and high specific surface area wherein said ezetimibe micro-particles are prepared without a micronization process. The suspension is obtained by dissolving ezetimibe in a solvent, precipitating ezetimibe by an anti-solvent, recovering the obtained precipitate, drying said precipitate then re-suspending the dried precipitate in a solvent and homogenizing the obtained suspension.
The processes according to the state of the art increase the bioavailability of ezetimibe by using amorphization or micronization. Said processes involve several drawbacks and difficulties.
The amorphous form due to the high free energy is inclined on the one hand to transform into crystalline form resulting unreproducible and deteriorating dissolution rate and bioavailability, on the other hand the chemical stability of the amorphous form is lower. Therefore in order to maintain the amorphous form special excipients and processing are generally necessary.
Micronization, which is often used for increasing the dissolution rate of ezetimibe, increases the free energy of the active ingredient significantly, resulting in the deterioration of the chemical stability; it causes dusting, significant product loss and is therefore an environmental load. Furthermore electrostatic charge accumulates in the micronized active ingredient and due to the electrostatic repulsion between the particles, a product with low mass-density is obtained, which is less suitable for further processing.
A dissolution rate and bioavailability suitable for manufacturing pharmaceutical compositions can be achieved with crystalline ezetimibe without a micronization process. Thus the increase of free energy, deterioration of chemical stability, accumulation of electrostatic charge in particles and occurrence of environmental and industrial health damage can be avoided. Such process is described in WO2009/077573 international patent application, which eliminates the above mentioned drawbacks, but this complicated multi-step process is unsuitable for industrial scale manufacturing of microcrystalline ezetimibe containing suspension without using a micronization process. Furthermore in the suspension the particle size of ezetimibe varies in wide ranges when using in WO2009/077573 disclosed process and the particle size distribution can be considered extremely heterogenic.